1,2-dihydroquinolines are key intermediates in the preparation of a number of steroid receptor modulating compounds, and are prepared by a multi-step route culminating in the treatment of an aniline with acetone and iodine at elevated temperatures in a process known as the Skraup reaction, as shown below. See R. H. F. Manske et al., Organic Reactions 7: 59-98 (1953), and W. R Vaughan, Org. Synth. Coll. Vol III, 329-332 (1955). ##STR1## Many 1,2-dihydroquinolines are themselves steroid receptor modulating compounds. See, for example, PCT Int'l Publ. No. WO 96/19458; U.S. Pat. No. 5,693,647. Application of the traditional Skraup reaction to the synthesis of many of these 1,2-dihydroquinolines is problematic in that large quantities of a number of tarry by-products are formed that must be removed prior to use in further synthetic transformations, and the yields are generally low (15-50%). For example, as shown in U.S. Pat. No. 5,693,647, treatment of a polycyclic aniline, such as the amino-chloro-benzocoumarin shown below, with acetone and iodine at 130-135.degree. C. affords only an 18% yield of the corresponding 1,2-dihydroquinoline. Furthermore, purification is very difficult due to the aforementioned by-product formation. ##STR2##
Several catalysts other than iodine have been reported to mediate the Skraup reaction such as iron trichloride, boron trifluoride, hydrofluoric acid, hydrochloric acid, p-toluenesulfonic acid, benzene sulfonic acid, and other acids, sometimes with less by-product formation. In addition, acidic ionic exchange resins have been used as catalysts, with improved yields of dihydroquinoline products. However, iodine has provided the most efficient synthesis of polycyclic 1,2-dihydroquinolines thus far. See, for example, U.S. Pat. Nos. 4,746,743, 4,514,570, and 3,829,292.
Therefore, a method for obtaining 1,2-dihydroquinolines in high yield with a significant reduction in the formation of by-products is needed, as compared to the traditional Skraup reaction.
The entire disclosures of the publications and references referred to above and hereafter in this specification are incorporated herein by reference.